We propose a series of translational studies using in vivo magnetic resonance (MR) neuroimaging and spectroscopy applied across rats and humans and monkeys by a collaboration between INIA-West and INIA-Stress. The goal is to identify and explicate changes in brain morphology, neurocircuitry, and metabolism during the development and maintenance of alcohol dependence. Exploratory studies will include correlation of in vivo MR data with postmortem histological analyses in collaboration with other INIA-West sites. Specific Aim 1: Rat Model of Dependence-Induced Drinking and Neuroadaptation. A primary INIA animal model of high alcohol consumption is withdrawal induced-drinking demonstrated with repeated high dose binge exposure, analogous to the chronic intermittent ethanol (CIE) paradigm. The progression of brain circuitry change over the course of repeated exposure-withdrawal cycles will be demonstrable with functional neuroimaging and a change in the pattern of choline and glutamate levels. Specific Aim 2: Rat-Monkey-Human Translation of High Doses of Chronic Alcohol: Brain Structure and Intrinsic Neural Connectivity. We propose parallel studies in chronic alcoholics and chronically-exposed animals using analogous neuroimaging probes: structural morphometry (MRI) and fcMRI from nodes pertinent to the maintenance of alcohol dependence-"withdrawal/negative affect" circuitry. We will use a longitudinal design, and a common analysis to be conducted across species: rat, monkey, and human. Specific Aim 3: Rat-Monkey-Human Translation of High Doses of Chronic Alcohol: Brain Metabolites. In vivo MR spectroscopy (MRS) studies report abnormally high choline soon after alcohol withdrawal in human alcoholics and rats chronically exposed to alcohol and in rats with single binge exposures. High glutamate occurs with high chronic alcohol exposure. As potential markers of dependence, we will model this pattern of metabolite changes in collaboration with INIA-Stress and propose parallel rat, monkey, and human studies using a common MRS acquisition and analysis tuned specifically to detect glutamate. The proposed research conceptually casts some alcoholic brain damage as a disorder of neuroconnectivity with structural and functional concomitants with bidirectional translation from humans to animal models and back to humans. We bring forth a paradigm shift from observing the brain's responsivity to external demands to investigating the brain's ongoing intrinsic activity as a concept for explicating the deleterious effects of chronic alcoholism on the brain. PUBLIC HEALTH RELEVANCE: Neuroadaptation is the process by which continued consumption of alcohol, initially rewarding, is replaced by "withdrawal/negative affect" and ultimately dependence, a condition with serious public health consequences. Processes involved in the transition from reversible to sustained changes are unknown but our proposed work will translate findings from rats and monkeys to humans to enable a mechanistic understanding of the development of dependence.